Early Aids Cases

This very important article by Lawerence Altman reopens the
debate on the origins of HIV. These early cases played a crucial
role in 'disproving' the possible laboratory origin of HIV.
- Carl
---------- FAIR USE ONLY -----------
Earliest AIDS Case Is Called Into Doubt
By LAWRENCE K. ALTMAN
The New York Times
April 4, 1995, Tuesday, Late Edition - Final
Section C; Page 1; Column 1
WHAT was believed to be the earliest known case of AIDS, dating
to 1959, may not have been AIDS after all, new scientific evidence
shows.
The case of David Carr, a 25-year-old man who died in 1959 in
Manchester, England, has taken another perplexing twist.
Mr. Carr's mysterious symptoms, which were so extraordinary that
his doctors wrote up his case in 1960 in an international medical
journal, The Lancet, and saved many samples from his organs, were
identified in 1990 as resulting from AIDS. This made Mr. Carr's the
earliest well-documented case of AIDS and promised to help
establish the history of the epidemic.
The AIDS epidemic was first recognized in 1981, in the United
States. But it was not until 1990 that two University of Manchester
doctors, George Williams and Gerald Corbitt, were able to use the
then-new polymerase chain reaction technique to analyze Mr. Carr's
stored tissues for H.I.V., the virus that causes AIDS. The P.C.R.
technique amplifies tiny bits of DNA hundreds of times in a few
minutes. Identifying part of the sequence of H.I.V. in the DNA
extracted from the tissue cells, they reported, again in The Lancet,
that Mr. Carr's strange malady was AIDS.
The dating of the Manchester AIDS case had several nonscientific
consequences. It appeared to give the lie to a theory being put
about by the Soviet K.G.B. that H.I.V. had escaped from an American
germ warfare laboratory. Its early date seemed to contradict a
theory advanced in Rolling Stone that AIDS originated in the polio
vaccines tested in Africa in the late 1950's. And the case could be
cited as evidence that AIDS was abroad in the Western world well
before the epidemic appeared among gay men in the United States.
The find had scientific value as well, in that it would allow
researchers to assess the pattern of evolution of the fast-mutating
organism, by comparing th e 1959 strain with current strains. In
such work, scientists use computers to construct phylogenetic, or
family, trees comparing various strains of H.I.V.
"That is why we went after it so hard," said Dr. David Ho, who
decided to analyze the virus sequence in further detail. Dr. Ho heads
the Aaron Diamond AIDS Research Center in New York City and
was a member of a panel that refuted the polio vaccine theory in
1992. He wrote to Dr. Corbitt in July 1992 to ask for samples of Mr.
Carr's stored tissues, and later he asked Dr. Williams for more.
But to Dr. Ho's amazement, he could isolate H.I.V. from only one
sample that the British researchers sent him, and the genetic map
made of the virus's fingerprints differed so much from what he
expected that he went on to do even more tests.
Most critically, the additional tests showed the tissues sent to Dr.
Ho were from at least two people.
Something is badly wrong with the Manchester results, in Dr. Ho's
view, but whatever it is, there is no longer any proof that Mr. Carr
died of AIDS. University of Manchester officials strongly reject Dr.
Ho's findings. Prof. James Burnie, a professor of bacteriology at the
university who was not an author of the 1990 report, said in a
statement:
"There is no doubt the original findings as reported in The
Lancet in July 1990 were correct. We have already carried out
an informal inquiry which has validated this."
But the university is planning further investigations, the statement
said, and in a brief interview, Professor Burnie said, "The issue is not
anywhere near dead."
Dr. Ho is sure of his findings, which are to be published soon in
Nature.
Details of his work were described in The Independent of London
last month.
In the first set of material, Dr. Ho found H.I.V.-1, the dominant type
of AIDS virus in the world, in DNA extracted from Mr. Carr's kidney.
But although he found no virus in DNA from the bone marrow, he
passed over the finding because his focus was on identifying the
molecular sequences and comparing them to those found in
Manchester.
"They matched up, and we were happy with that," Dr. Ho said.
It was only after Dr. Ho and his assistant, Dr. Tuofu Zhu, achieved
their main goal, a genetic map of the virus from the samples
provided by Dr. Corbitt, that he began to notice puzzling findings.
The 1959 strain, he found, bore a close resemblance to strains of
H.I.V. isolated from contemporary patients.
"We couldn't make any sense of this," Dr. Ho said. So he sent the
data to Dr. Gerald Myers, who runs an H.I.V. sequence data bank at
the Los Alamos National Laboratory in New Mexico and to Dr. Eddie
Holmes at Oxford University in England.
Dr. Myers and Dr. Holmes agreed that the strain was not
consistent with what they would expect a 1959 virus to look like. "It
was aberrant," Dr. Myers said in an interview.
H.I.V. mutates constantly. A strain dating from 1959 would be
expected to look different from 1990 strains. But few such differences
could be seen, Dr. Myers said.
Only a small group of experts knew about Dr. Ho's genetic map
of the virus -- and only now is it being made available to scientists
through the LosAlamos data bank. One of those who saw it earlier
was Dr. Beatrice Hahn, an expert in the evolution of AIDS viruses at
the University of Alabama in Birmingham, who urged Dr. Ho to dig
harder.
Dr. Myers asked Dr. Ho if he was sure the virus he saw was not
a contaminant from his own laboratory. Dr. Ho pointed out that the
laboratory in Manchester had found the same sequence, meaning
that "any contamination could not have occurred in our laboratory,"
he said.
"They got the same sequence in Manchester and Dr. Corbitt said
the work was done in a laboratory that never processed H.I.V," Dr.
Ho said.
"We wanted it to be true," Dr. Ho said, adding that he initially
resisted Dr. Myers's skepticism. Valid findings would "mean that the
virus had not changed much in 30 years, indicating the virus had
been with us for centuries."
To resolve the issue, Dr. Ho's team needed to test the actual
tissue, not repeat tests on the original shipment of DNA. So in
November 1993 Dr. Ho asked Dr. Williams for more samples. Dr.
Williams did not send them until February 1994.
Dr. Ho extracted DNA and used P.C.R. to isolate H.I.V. and similar
viruses from each of seven tissues from different organs sent by Dr.
Williams and four sent by Dr. Corbitt. But Dr. Ho's team could detect
no virus after many attempts in any of the second batch of tissues.
The tests did identify a globin gene present in all cells in both sets
of samples, an indication that the tissue had not totally decayed.
"We had to conclude that we could not verify the initial results with
the new set of tissues," Dr. Ho said.
To investigate the discrepancy, his team undertook forensic tests
to identify genetic markers on both the original and the second
shipment of material, Dr. Ho said.
There was no match. One explanation might have been that
contamination had occurred when, say, a knife used to cut one
specimen was not cleaned before use on a second specimen. But
the British scientists said they had taken precautions to avoid such
problems.
Only one explanation remained, Dr. Ho said: "We had to conclude
that the material came not from one person but at least two
individuals." Dr. Ho's only isolation of H.I.V. was from a kidney DNA
sample that appears to have been contaminated by another clinical
specimen. "Whether that is an accident or something else we have
no way of saying," Dr. Ho said.
Clearly, the findings "raise serious doubts about the authenticity of
the 1959 case," Dr. Ho said.
Dr. Myers said that if all the tissues supplied in the second set are
indeed shown to be tissues from Mr. Carr, as seems likely, "then he
never had AIDS."
But AIDS is not completely eliminated because the techniques, as
advanced
as they are, may not be able to detect H.I.V. in tissue that has been
stored for 35 years, Dr. Ho said.
"There are a lot of discrepancies that need to be explained," he
said.
Dr. Ho said Dr. Corbitt had written him saying he wanted to be a
co-author of a retraction of the 1990 Lancet report because the
findings were invalidated by the latest tests. But Dr. Corbitt said he
could not comment beyond the news release, as requested by his
employer, the Central Manchester Healthcare Trust. Dr. Williams
could not be located. Dr. Ho said that it would take another
scientific team several months to confirm or reject his findings, and
that he was eager for such an effort to be made.
Dr. Robin Weiss, an AIDS virus expert at the Institute of Cancer
Research in London, said in an interview that he had written to the
University of Manchester offering to undertake the project.
Professor Burnie said the Manchester team was trying to decide
which scientists would be acceptable to both sides to undertake
confirmation studies. "It's very awkward," he said.
The Trust and University of Manchester have asked Dr. Ho to
return the samples. Dr. Ho said he had agreed, though so much was
used up in the testing that "we are looking at practically empty vials."
"The best thing would be to send the stuff directly to the
independent scientist rather than sending it back to Manchester," Dr.
Ho said. "The Manchester team could get new material and send it
directly to that independent laboratory."
Mr. Carr's body was cremated, so there is no way to get new
samples. But several scientists said his lung tissue, which is believed
to be still stored in Manchester, could be re-examined for evidence
of a fungus, Pneumocystis carinii, and the cytomegalovirus. Both
were identified in the autopsy report. If the stored sample checks out
as being Mr. Carr's, it could be tested for H.I.V.
There are many theories about the origins of AIDS. A prevailing
belief is that H.I.V. was around for a long time and that on many
occasions humans became infected when they killed monkeys or
other primates for food. Because the infection took place in remote
areas and the virus was not transmitted to anyone, or only to a few
others, such cases would have gone undetected.
But, the theory holds, in the late 1950's as society became more
mobile, transmission of the virus increased tremendously. Many
people moved from remote areas to cities, practicing free sex and
health workers used contaminated needles.
AIDS "either came from naturally infected chimpanzees or from a
third species of monkeys that gave it independently to humans and
chimps," said Dr. Hahn, an expert in the evolution of AIDS viruses.
But others believe H.I.V. resulted from a recent mutation of a
formerly benign virus.
Another very early case of H.I.V. infection was in an individual in
Zaire, who was part of a study conducted in 1959 for other
purposes. Blood tests performed by four laboratories have found
evidence of H.I.V.-1, said Dr. Andre J. Nahmias of Emory University
who oversaw the testing, but no effort was made to isolate the virus.
Contrary to widespread belief, a small amount of that individual's
blood does exist. It is in a freezer in Atlanta, Dr. Nahmias said in an
interview. Because the techniques used in culturing and sequencing
H.I.V. have been improving rapidly, Dr. Nahmias said he would not
yield any of "the precious little serum in the vial" until he found the
scientist who had the best method for such tests. If the sequencing
is done, it could provide the information scientists had sought in Mr.
Carr's case.
For now, the oldest documented case of AIDS from which H.I.V.
has been sequenced is a 1976 case in Zaire, Dr. Myers said.
--
- Carl